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• W4386423764 endingPage "7720" @default.
• W4386423764 startingPage "7708" @default.
• W4386423764 abstract "Aggregation of p53 mutants can result in loss-of-function, gain-of-function, and dominant-negative effects that contribute to tumor growth. Revealing the mechanisms underlying mutation-enhanced p53 aggregation and dissecting how small molecule inhibitors prevent the conversion of p53 into aggregation-primed conformations are fundamentally important for the development of novel therapeutics for p53 aggregation-associated cancers. A recent experimental study shows that resveratrol (RSV) has an inhibitory effect on the aggregation of hot-spot R248Q mutant of the p53 core domain (p53C), while pterostilbene (PT) exhibits a relatively poor inhibitory efficacy. However, the conformational properties of the R248Q mutant leading to its enhanced aggregation propensity and the inhibitory mechanism of RSV against p53C aggregation are not well understood. Herein, we performed extensive all-atom molecular dynamics simulations on R248Q p53C in the absence and presence of RSV/PT, as well as wild-type (WT) p53C. Our simulations reveal that loop L3, where the mutation resides, remains compact in WT p53C, while it becomes extended in the R248Q mutant. The extension of loop L3 weakens the interactions between loop L3 and two crucial aggregation-prone regions (APRs) of p53C, leading to impaired interactions within the APRs and their structural destabilization as well as p53C. The destabilized APRs in the R248Q mutant are more exposed than in WT p53C, which is conducive to p53C aggregation. RSV has a higher preference to bind to R248Q p53C than PT. This binding not only stabilizes loop L3 of R248Q mutant to its WT-like conformation, preventing L3-extension-caused APRs’ destabilization but also reduces APRs’ solvent exposure, thereby inhibiting R248Q p53C aggregation. However, PT exhibits a lower hydrogen-bonding capability and a higher self-association propensity, which would lead to a reduced p53C binding and a weakened inhibitory effect on R248Q mutant aggregation. Our study provides mechanistic insights into the R248Q mutation-enhanced aggregation propensity and RSV’s potent inhibition against R248Q p53C aggregation." @default.
• W4386423764 created "2023-09-05" @default.
• W4386423764 creator A5000510528 @default.
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• W4386423764 creator A5013846158 @default.
• W4386423764 creator A5091115474 @default.
• W4386423764 date "2023-09-04" @default.
• W4386423764 modified "2023-09-30" @default.
• W4386423764 title "Elucidating the Mechanisms of R248Q Mutation-Enhanced p53 Aggregation and Its Inhibition by Resveratrol" @default.
• W4386423764 cites W1031578623 @default.
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• W4386423764 cites W1967058595 @default.
• W4386423764 cites W1971689309 @default.
• W4386423764 cites W1976499671 @default.
• W4386423764 cites W1978498560 @default.
• W4386423764 cites W1980396417 @default.
• W4386423764 cites W1985271346 @default.
• W4386423764 cites W1986076152 @default.
• W4386423764 cites W1986267130 @default.
• W4386423764 cites W1986503899 @default.
• W4386423764 cites W1995068068 @default.
• W4386423764 cites W2005918656 @default.
• W4386423764 cites W2007236469 @default.
• W4386423764 cites W2008708467 @default.
• W4386423764 cites W2011862049 @default.
• W4386423764 cites W2013136213 @default.
• W4386423764 cites W2017954949 @default.
• W4386423764 cites W2040740978 @default.
• W4386423764 cites W2046345348 @default.
• W4386423764 cites W2047596219 @default.
• W4386423764 cites W2057477511 @default.
• W4386423764 cites W2060513486 @default.
• W4386423764 cites W2061245389 @default.
• W4386423764 cites W2067174909 @default.
• W4386423764 cites W2073576377 @default.
• W4386423764 cites W2077000240 @default.
• W4386423764 cites W2093775600 @default.
• W4386423764 cites W2093865758 @default.
• W4386423764 cites W2094186244 @default.
• W4386423764 cites W2096276671 @default.
• W4386423764 cites W2108768863 @default.
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• W4386423764 cites W2118233996 @default.
• W4386423764 cites W2132188221 @default.
• W4386423764 cites W2138107646 @default.
• W4386423764 cites W2147993766 @default.
• W4386423764 cites W2166269098 @default.
• W4386423764 cites W2175728132 @default.
• W4386423764 cites W2207474307 @default.
• W4386423764 cites W2312641146 @default.
• W4386423764 cites W2341866865 @default.
• W4386423764 cites W2533536529 @default.
• W4386423764 cites W2555870966 @default.
• W4386423764 cites W2591390000 @default.
• W4386423764 cites W2601855059 @default.
• W4386423764 cites W2626046448 @default.
• W4386423764 cites W2690481485 @default.
• W4386423764 cites W2752942423 @default.
• W4386423764 cites W2777126867 @default.
• W4386423764 cites W2805180952 @default.
• W4386423764 cites W2810340031 @default.
• W4386423764 cites W2907307161 @default.
• W4386423764 cites W2908811118 @default.
• W4386423764 cites W2996248176 @default.
• W4386423764 cites W2999554785 @default.
• W4386423764 cites W3004119070 @default.
• W4386423764 cites W3013763244 @default.
• W4386423764 cites W3113491107 @default.
• W4386423764 cites W3126550244 @default.
• W4386423764 cites W3127602688 @default.
• W4386423764 cites W3135012715 @default.
• W4386423764 cites W3163638763 @default.
• W4386423764 cites W3174122508 @default.
• W4386423764 cites W3194505515 @default.
• W4386423764 cites W3201356533 @default.
• W4386423764 cites W3217461331 @default.
• W4386423764 cites W4210383412 @default.
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• W4386423764 doi "https://doi.org/10.1021/acs.jpcb.3c04700" @default.
• W4386423764 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37665658" @default.
• W4386423764 hasPublicationYear "2023" @default.
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